How Lantus Works:

LANTUS^® is a recombinant human insulin analog that is a long-acting, , parenteral blood-glucose-lowering agent. The activity of LANTUS results in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile is what allows LANTUS to be dosed once a day as a patient's basal insulin. LANTUS provides a continuous level of insulin, similar to the slow, steady (basal) secretion of insulin provided by the normal pancreas. For optimal control, LANTUS may need to be prescribed in combination with short-acting insulins or oral hypoglycemic agents. Lantus is available by prescription only.

Lantus differs from other insulins in that asparagine at position A21 is replaced by glycine, and two arginines are added to the C-terminus of the B-chain. Like other insulins, insulin glargine stimulates peripheral glucose uptake, especially by skeletal muscle and fat, and inhibits glucose production. Lantus is stored at an acidic pH. Lantus is not soluble at neutral pH, and precipitates when injected subcutaneously. Microprecipitates formed in the subcutaneous tissue after injection slow the absorption of insulin glargine. This provides a relatively constant level over 24 hours with no pronounced peak.¹

Lantus is indicated for once-daily subcutaneous administration at bedtime for adults and children six years of age and older with type 1 diabetes mellitus or adults with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.¹

Lantus is available in 10 mL vials which contain insulin glargine 100 international units (IU)/mL.¹

The potency of Lantus is similar to human insulin. LANTUS^® should be administered subcutaneously once a day at bedtime. LANTUS is not intended for intravenous administration. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia.

The desired blood glucose levels as well as the doses and timing of antidiabetic medications must be determined individually. Blood glucose monitoring is recommended for all patients with diabetes.

As with all insulins, injection sites within an injection area (abdomen, thigh or deltoid) must be rotated from one injection to the next.

In clinical studies, there was no relevant difference in LANTUS absorption after abdominal, deltoid, or thigh subcutaneous administration. A patient starter kit with complete instructions for self-injection, as well as a detailed brochure on LANTUS and diabetes is available for distribution to your patients. Please contact your local Aventis Pharmaceuticals representative for more information.

LANTUS MUST NOT BE DILUTED OR MIXED WITH ANY OTHER INSULIN OR SOLUTION. If mixed or diluted, the solution may become cloudy, and the onset of action/time to peak effect may be altered in an unpredictable manner.

Close monitoring is required when starting insulin glargine or changing a patient from other types of insulin.¹

In insulin-naïve patients with type 2 diabetes, the average starting dose in clinical trials was 10 IU SC at bedtime. Doses were titrated based on blood glucose, and the total daily dose ranged from 2 IU to 100 IU.¹

When changing a patient (child > 6 years or adult) from intermediate- or long-acting insulin, the amount of short-acting insulin or oral antidiabetic agent may need to be adjusted. In premarketing studies, for patients using once-daily NPH or Ultralente insulin, the initial dose of insulin glargine was not changed. For patients using twice-daily NPH insulin, the initial once-daily, bedtime dose of insulin glargine was reduced by 20% and then adjusted based on the patient’s response.¹

It is important to counsel patients on the proper storage of insulin. Tell patients that Lantus 10 mL vials can be kept at room temperature for 28 days. Remind patients to keep all insulins away from direct heat and light.¹

Like all insulin formulations, hypoglycemia is the most common adverse effect. The timing of hypoglycemia may differ among various formulations of insulin. The prolonged effect of subcutaneous insulin glargine may result in more prolonged hypoglycemia. Glucose monitoring is recommended.¹

As with any insulin therapy, localized lipodystrophy may occur and can be minimized by rotation of the injection site. Most minor reactions resolve within a few days. Pain at the injection site is more common with insulin glargine than NPH insulin (2.7% versus 0.7%, respectively- which would mean about 1 in 40 patients due to its acidic pH). . Reports of pain were usually mild and transient and no one discontinued therapy due to this side effect.¹

Insulin therapy may cause sodium and water retention, especially if previously poor metabolic control is improved by intensified insulin therapy. Although immediate-type allergic reactions to insulin are rare, they have been reported with Lantus. These reactions can be life-threatening and are characterized by generalized skin reactions, angioedema, bronchospasm, hypotension, or shock.¹

To lessen the risk of hypoglycemia, LANTUS patients switched from NPH should have their previous total daily NPH dose reduced by 20%

The following table lists drugs that can affect glucose metabolism and, therefore, may require insulin dosage adjustments:¹

Drugs that increase the blood-glucose lowering effect and may result in hypoglycemia: Oral antidiabetic agents, fibrates, angiotensin-converting enzyme inhibitors, disopyramide, sulfonamide antibiotics, , fluoxetine, monoamine oxidase inhibitors, propoxyphene, salicylates, somatostatin analogs.

Drugs that decrease the blood-glucose lowering effect and may result in hypoglycemia: Corticosteroids, somatotropin, diuretics, sympathomimetic agents (e.g., epinephrine, terbutaline albuterol), isoniazid, phenothiazine derivatives, thyroid hormones, estrogens, progestogens, danazol

Drugs that have a variable effect on blood glucose Drugs that have a variable effect on blood glucose: Alcohol, Beta-blockers, clonidine, lithium, pentamidine

Combination Therapy

LANTUS^® delivers excellent basal glucose control in combination with oral hypoglycemic agents, or as part of a regimen with short-acting regular insulin. LANTUS does this by providing a continuous level of insulin, similar to the slow, steady (basal) secretion of insulin provided by the normal pancreas. For optimal control, LANTUS may need to be prescribed in combination with short-acting insulins’ or oral hypoglycemic agents.

One novel approach would be to use Lantus® for the basal insulin and use one of the meglitinides as Prandin® or Starlix® to increase insulin release for each meal.

Lantus is contraindicated in patients hypersensitive to insulin glargine or any of its components.¹

Lantus should not be given by the intravenous route. Insulin glargine produces a long-acting effect by forming microprecipitates in the subcutaneous tissue. Administration of the total daily dose of Lantus by the intravenous route may result in hypoglycemia.¹

Lantus must not be diluted or mixed with any other insulin or solution. If it is diluted or mixed, the pharmacokinetic and/or pharmacodynamic profile of Lantus, or the mixed insulin, may be altered. In animals, when Lantus was mixed with regular insulin, the regular insulin showed a delayed onset of action and delayed time to maximum effect. The total bio-availability of the mixture was also slightly decreased.¹

Pregnancy Category C.¹ In animal studies, the effects of insulin glargine did not differ from those observed with regular human insulin. There are no well-controlled studies of Lantus in pregnant women.

Aventis Pharmaceuticals Inc, Kansas City, MO 64137; telephone (888) 242-9321; www.aventispharma-us.com.

With the introduction of glargine, we now have an interesting list of possible new combinations using oral and injectable therapies.

Patient counseling is very important when having them start any new therapy especially for insulin. Several studies have shown insulin glargine to be at least as safe and effective as NPH insulin. One study looked at 619 patients with type 1 diabetes controlled on NPH insulin and insulin lispro. Patients received either insulin glargine once daily or NPH insulin once or twice daily. Patients continued to use insulin lispro before meals. After 16 weeks, insulin glargine produced a greater reduction in fasting blood glucose levels than NPH insulin. More patients receiving insulin glargine (29.6%) than NPH insulin (16.8%) achieved the target fasting blood glucose level of less than 120.7 mg/dL. However, glycosylated hemoglobin levels were similar at the end of the study for both groups. The frequency of hypoglycemia was similar for both treatment groups, and there was less weight gain reported in patients taking insulin glargine than in those taking NPH insulin.²

Another study in 256 patients with type 1 diabetes reported lower and more stable fasting blood glucose levels with the use of insulin glargine than with twice daily NPH insulin. Interestingly, fewer patients taking NPH insulin (93%) reported hypoglycemia than patients taking insulin glargine (97%).³

The efficacy of insulin glargine has also been studied in patients with type 2 diabetes. Insulin glargine was compared to NPH insulin in 425 patients with type 2 diabetes. These patients were already receiving oral antidiabetic drugs, but were poorly controlled. Patients were randomized to receive insulin glargine or NPH insulin daily at bedtime in addition to their oral medications. Control of blood sugar was similar for patients receiving both drugs. HgA1c values after one year were 8.3% and 8.2% for insulin glargine and NPH insulin, respectively. HgA1c values for patients who achieved the target glucose level of 120 mg/dL were 7.7% and 7.6% for insulin glargine and NPH insulin, respectively. Insulin glargine caused less nocturnal hypoglycemia than NPH insulin, and there was no difference in weight gain between the two treatment groups.⁴

There has been a continuing search for ways to mimic normal physiologic insulin secretion in patients with diabetes. There are a variety of types of insulin available today, all with different pharmacokinetic properties. However, the products currently on the market fall short of duplicating the basal insulin secretion seen in healthy individuals. Intermediate- and long-acting insulins currently available are often associated with a duration of action too short to allow for once-daily dosing. They also often result in a peaking of insulin levels, which can cause hypoglycemia. In addition, there can be a high variablility of the hypoglycemic effect from day to day, due to unpredictable absorption from subcutaneous tissue.²

Insulin glargine makes an attempt to improve on some of the deficiencies in previously available insulins. It seems to produce a less variable effect on fasting glucose levels, suggesting that it has more predictable absorption than NPH insulin. It also has a peakless action profile, causes less nighttime hypoglycemia, and is conveniently dosed once a day.^2,4 However, insulin glargine does cause a greater incidence of pain at the injection site than NPH insulin. Another disadvantage of insulin glargine is that it cannot be mixed with any other insulin or solution.¹

Lantus provides a good alternative to NPH and Ultralente insulins. As with any insulin, the dose of Lantus is individualized according to each patient’s needs. The average starting dose in studies for patients with type 2 diabetes on oral hypoglycemic drugs was 10 IU daily. Remember that dose adjustments may be necessary when converting from once daily intermediate- or long-acting insulins to Lantus. Also remember to reduce the dose by 20% when switching from TWICE daily intermediate- or long-acting insulins to Lantus.

Lantus is in a taller and skinner bottle then the most common insulins’ that will help to distinguish it for patients with visual difficulties. It is a clear solution, just like regular insulin and lispro insulin. Patients often differentiate their "long-acting" insulin by the fact that is it "cloudy." With the addition of a "clear, long-acting" insulin, confusion on the patient’s part is inevitable. Patient counseling will be vital to prevent medication administration errors. Also be careful to avoid errors by confusing "Lantus" with "Lente" or "lispro."

1. Aventis Pharmaceuticals, Inc. Full prescribing information for Lantus. April 2000.

2. Raskin P, Klaff L, Bergenstal R, et al. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care 2000;23:1666-1671. www.lantus.com

3. Rosenstock J, Park G, Zimmerman J. Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. Diabetes Care 2000;23:1137-1142.

4. Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000;23:1130-1136.